Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease

TY - JOUR

T1 - Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease

AU - Frikke-Schmidt, R.

AU - Nordestgaard, B.G.

AU - Stene, M.C.A.

AU - Sethi, A.A.

AU - Remaley, A.T.

AU - Schnohr, P.

AU - Grande, P.

AU - Tybjaerg-Hansen, A.

N1 - Times Cited: 0ArticleEnglishTybjaerg-Hansen, AUniv Copenhagen Hosp, Dept Clin Biochem, Mol Genet Sect, Rigshosp, KB3011,Blegdamsvej 9, DK-2100 Copenhagen O, DenmarkCited References Count: 59308ARAMER MEDICAL ASSOC515 N STATE ST, CHICAGO, IL 60610-0946 USACHICAGO

PY - 2008

Y1 - 2008

N2 - Context Low levels of high- density lipoprotein ( HDL) cholesterol are inversely related to cardiovascular risk. Whether this is a causal effect is unclear. Objective To determine whether genetically reduced HDL cholesterol due to heterozygosity for 4 loss- of- function mutations in ABCA1 cause increased risk of ischemic heart disease ( IHD). Design, Setting, and Participants Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study ( CCHS), a 31-year prospective general population study ( n= 9022; 28 heterozygotes); the Copenhagen General Population Study ( CGPS), a cross- sectional general population study ( n= 31 241; 76 heterozygotes); and the Copenhagen Ischemic Heart Disease Study ( CIHDS), a case- control study ( n= 16 623; 44 heterozygotes). End points in all 3 studies were recorded during the period of January 1, 1976, through July 9, 2007. Main Outcome Measures Levels of HDL cholesterol in the general population, cellular cholesterol efflux, and the association between IHD and HDL cholesterol and genotype. Results Heterozygotes vs noncarriers for 4 ABCA1 mutations ( P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/ dL ( interquartile range, 31- 50 mg/ dL) vs 58 mg/ dL ( interquartile range, 46- 73 mg/ dL), corresponding to a reduction in HDL cholesterol of 17 mg/ dL ( P <. 001). A 17- mg/ dL lower HDL cholesterol level in the CCHS was associated with a multifactorially adjusted hazard ratio for IHD of 1.70 ( 95% confidence interval [ CI], 1.57- 1.85). However, for IHD in heterozygotes vs noncarriers, the multifactorially adjusted hazard ratio was 0.67 ( 95% CI, 0.28-1.61; 1741 IHD events) in the CCHS, the multifactorially adjusted odds ratio was 0.82 ( 95% CI, 0.34- 1.96; 2427 IHD events) in the CGPS, and the multifactorially adjusted odds ratio was 0.86 ( 95% CI, 0.32- 2.32; 2498 IHD cases) in the CIHDS. The corresponding odds ratio for IHD in heterozygotes vs noncarriers for the combined studies ( n= 41 961; 6666 cases; 109 heterozygotes) was 0.93 ( 95% CI, 0.53- 1.62). Conclusion Lower plasma levels of HDL cholesterol due to heterozygosity for loss-of-function mutations in ABCA1 were not associated with an increased risk of IHD Udgivelsesdato: 2008/6/4

AB - Context Low levels of high- density lipoprotein ( HDL) cholesterol are inversely related to cardiovascular risk. Whether this is a causal effect is unclear. Objective To determine whether genetically reduced HDL cholesterol due to heterozygosity for 4 loss- of- function mutations in ABCA1 cause increased risk of ischemic heart disease ( IHD). Design, Setting, and Participants Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study ( CCHS), a 31-year prospective general population study ( n= 9022; 28 heterozygotes); the Copenhagen General Population Study ( CGPS), a cross- sectional general population study ( n= 31 241; 76 heterozygotes); and the Copenhagen Ischemic Heart Disease Study ( CIHDS), a case- control study ( n= 16 623; 44 heterozygotes). End points in all 3 studies were recorded during the period of January 1, 1976, through July 9, 2007. Main Outcome Measures Levels of HDL cholesterol in the general population, cellular cholesterol efflux, and the association between IHD and HDL cholesterol and genotype. Results Heterozygotes vs noncarriers for 4 ABCA1 mutations ( P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/ dL ( interquartile range, 31- 50 mg/ dL) vs 58 mg/ dL ( interquartile range, 46- 73 mg/ dL), corresponding to a reduction in HDL cholesterol of 17 mg/ dL ( P <. 001). A 17- mg/ dL lower HDL cholesterol level in the CCHS was associated with a multifactorially adjusted hazard ratio for IHD of 1.70 ( 95% confidence interval [ CI], 1.57- 1.85). However, for IHD in heterozygotes vs noncarriers, the multifactorially adjusted hazard ratio was 0.67 ( 95% CI, 0.28-1.61; 1741 IHD events) in the CCHS, the multifactorially adjusted odds ratio was 0.82 ( 95% CI, 0.34- 1.96; 2427 IHD events) in the CGPS, and the multifactorially adjusted odds ratio was 0.86 ( 95% CI, 0.32- 2.32; 2498 IHD cases) in the CIHDS. The corresponding odds ratio for IHD in heterozygotes vs noncarriers for the combined studies ( n= 41 961; 6666 cases; 109 heterozygotes) was 0.93 ( 95% CI, 0.53- 1.62). Conclusion Lower plasma levels of HDL cholesterol due to heterozygosity for loss-of-function mutations in ABCA1 were not associated with an increased risk of IHD Udgivelsesdato: 2008/6/4

M3 - Journal article

SN - 0098-7484

VL - 299

SP - 2524

EP - 2532

JO - J A M A: The Journal of the American Medical Association

JF - J A M A: The Journal of the American Medical Association

IS - 21

ER -